This invention relates to a novel group of pyximidine compounds, processes for the preparation thereof, the use thereof in treating cytokine mediated diseases and pharmaceutical compositions for use in such therapy.
Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are biological substances produced by a variety of cells, such as monocytes or macrophages. IL-1 has been demonstrated to mediate a variety of biological activities thought to be important in immunoregulation and other physiological conditions such as inflammation [See, e.g., Dinarello et al., Rev. Infect. Disease, 6, 51 (1984)]. The myriad of known biological activities of IL-1 include the activation of T helper cells, induction of fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute phase proteins and the suppression of plasma iron levels.
There are many disease states in which excessive or unregulated IL-1 production is implicated in exacerbating and/or causing the disease. These include rheumatoid arthritis, osteoartritis, endotoxemia and/or toxic shock syndrome, other acute or chronic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease: tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reitefs syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, and acute synovitis. Recent evidence also links IL-1 activity to diabetes and pancreatic xcex2 cells.
Dinarello, J. Clinical Immunology, 5 (5), 287-297 (1985), reviews the biological activities which have been attributed to IL-1. It should be noted that some of these effects have been described by others as indirect effects of IL-1.
Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia, secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn""s disease, ulcerative colitis, or pyresis.
AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV). At least three types or strains of HIV have been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence of HIV infection, T-cell mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms. HIV entry into the T lymphocyte requires T lymphocyte activation. Other viruses, such as HIV-1, HIV-2 infect T lymphocytes after T Cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state to permit HIV gene expression and/or HIV replication. Monokines, specifically TNF, are implicated in activated T-cell mediated HIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with monokine activity such as by inhibition of monokine production, notably TNF, in an HIV-infected individual aids in limiting the maintenance of T cell activation, thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HIV infection. Monocytes, macrophages, and related cells, such as kupffer and glial cells, have also been implicated in maintenance of the HIV infection. These cells, like T-cells, are targets for viral replication and the level of viral replication is dependent upon the activation state of the cells. [See Rosenberg et al., The Immunopathogenesis of HIV Infection, Advances in Immunology, Vol. 57, (1989)]. Monokines, such as TNF, have been shown to activate HIV replication in monocytes and/or macrophages [See Poli, et. al., Proc. Natl. Acad. Sci., 87:782-784 (1990)], therefore, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T-cells.
TNF has also been implicated in various roles with other viral infections, such as the cytomegalia virus (CMV), influenza virus, and the herpes virus for similar reasons as those noted.
Interleukin-8 (IL-8) is a chemotactic factor first identified and characterized in 1987. IL-8 is produced by several cell types including mononuclear cells, fibroblasts, endothelial cells, and keratinocytes. Its production from endothelial cells is induced by IL-1, TNF, or lipopolysachharide (LPS). Human IL-8 has been shown to act on Mouse, Guinea Pig, Rat, and Rabbit Neutrophils. Many different names have been applied to IL-8, such as neutrophil attractantlactivation protein-1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor.
IL-8 stimulates a number of functions in vitro. It has been shown to have chemoattractant properties for neutrophils, T-lymphocytes, and basophils. In addition it induces histamine release from basophils from both normal and atopic individuals as well as lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b/CD18) on neuerophils without de novo protein synthesis, this may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many diseases are characterized by massive neutrophil infiltration. Conditions associated with an increased in IL-8 production (which is responsible for chemotaxis of neutrophils into the inflammatory site) would benefit by compounds which are suppressive of IL-8 production.
IL-1 and TNF affect a wide variety of cells and tissues and these cytokines as well as other leukocyte derived cytokines are important and critical inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
There remains a need for treatment, in this field. for compounds which are cytokine suppressive anti-inflaimnatory drugs, i.e. compounds which are capable of inhibiting cytokines, such as IL-1, IL-6, IL-8 and TNF.
This invention relates to the novel compounds of Formulas (I), (II), and (III) and pharmaceutical compositions comprising a compound of Formula (I), (II), or (III), respectively, and a pharmaceutically acceptable diluent or carrier.
This invention also relates to a method of inhibiting cytokines and the treaunent of a cytokine mediated disease, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I), (II), or (III).
This invention more specifically relates to a method of inhibiting the production of IL-1 in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I), (II), or (III).
This invention more specifically relates to a method of inhibiting the production of IL-8 in a mammal in need thereof which comprises administering to said mamrnal an effective amount of a compound of Formula (I), (II), or (III).
This invention more specifically relates to a method of inhibiting the production of TNF in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I), (II), or (III).
The novel compounds of this invention are represented by the structure having the formula: 
wherein:
R1 is 4pyridyl, 4pyrimidinyl, 4-quinazolinyl, 4-quinolyl, or 6-isoquinolinyl, which rings are optionally substituted with one or two substituents, each of which is independently selected from Y, NHRa, optionally substituted C1-4 alkyl, halogen, hydroxyl, optionally substituted C1-4 alkoxy, optionally substituted C1-4 alkylthio, C1-4 alkylsulfinyl, CH2OR12, anino, mono and di- C1-6 allyl substituted amino, or N(R10)C(O)Rb;
Y is X1xe2x80x94Ra;
X1 is oxygen or sulfur;
Ra is C1-6alkyl, aryl, arylC1-6alkyl, heterocyclic, heterocyclylC1-6 alkyl, heteroaryl, hetrroarylC1-6alkyl, wherein each of these moieties may be optionally substituted;
Rb is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4 alkyl, heterocyclyl, or heterocyclylC1-4 alkyl, wherein each of these moieties may be optionally substituted;
R2 is an optionally substituted auyl or optionally substituted heteroaryl group, provided that both R1 and R2 are not the same heteroaryl group;
and when R2 is an optionally substituted aryl ring, the ring is substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl or 5-naphth-2-yl substituent, is halo, cyano, xe2x80x94C(Z)NR13R14, xe2x80x94C(Z)OR23, xe2x80x94(CR10R20)n COR36, xe2x80x94SR15, xe2x80x94SOR15, xe2x80x94OR36, halo-substituted-C1-4 alkyl, C1-4 alkyl, xe2x80x94ZC(Z)R36, xe2x80x94NR10C(Z)R23, or xe2x80x94(CR10R20)n NR10R20 and which, for other positions of substitution, is halo, cyano, xe2x80x94C(Z)NR16R26, xe2x80x94C(Z)OR8, xe2x80x94(CR10R20)n COR8, xe2x80x94S(O)mR8, xe2x80x94OR8, halo-substituted-C1-4 alkyl, xe2x80x94C1-4 alkyl, xe2x80x94(CR10R20)nNR10C(Z)R8, xe2x80x94NHS(O)mR7, xe2x80x94NHS(O)mNR13R14, xe2x80x94NR7S(O)mR7, xe2x80x94NR7S(O)mxe2x80x2NR13R14 wherein m"" is 1 or 2, xe2x80x94ZC(Z)R8 or xe2x80x94(CR10R20)n NR16R26;
and when R2 is an optionally substituted heteroaryl group, the substituent groups include one or two substituents each of which is independently selected from C1-4 alkyl, halo, C1-4 alkoxy, C1-4 alkylthio, NR10R20, or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR12;
m is 0 or an integer of 1 or 2,
n is 0 or an integer of 1 or 2;
R3 is hydrogen, NR5R6, NHS(O)2R7, NR10C(Z)R8, NR10C(Z)NR5R6, NR10C(xe2x95x90NR11)NR5R6, or NR10C(Z)OR10; wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl moieties of R7, and R8 may be optionally substituted;
R5 and R6 are each independently selected from hydrogen or optionally substituted C1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9;
Z is oxygen or sulfur;
R7 is C1-10 alkyl, C3-7 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C1-10alkyl, heteroaryl or heteroarylalkyl;
R8 is hydrogen, C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl C1-10alkyl, aryl, arylC1-10 alkyl, heteroaryl or heteroarylC1-10 alkyl;
R9 is hydrogen, xe2x80x94C(Z)R8 or optionally substituted C1-10 alkyl, S(O)2R7, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl;
R10 and R20 is each independenty selected from hydrogen or C1-6 alkyl;
R11 is hydrogen, cyano, C1-4 alkyl, C3-7 cycloalkyl or aryl;
R12 is R10 or C(Z)xe2x80x94C1-4 alkyl, optionally substituted aryl, optionally substituted arylC1-4 alkyl, or S(O)2R7;
R13 and R14 is each independently selected from hydrogen or C1-4 alkyl or R13 and R14 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR22;
R15 is hydrogen, C1-4 alkyl C2-4 alkenyl, C2-4 alkynyl or NR13R14, provided that the moiety xe2x80x94SR15 is not xe2x80x94SNR13R14 and the moiety xe2x80x94S(O)R15 is not xe2x80x94SOH;
R16 and R26 is each independently selected from hydrogen or optionally substituted C1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR12;
R22 is R10 or C(Z)xe2x80x94C1-4 alkyl;
R23 is C1-4 alkyl halo-substituted-C1-4 alkyl, or C3-5 cycloalkyl;
R36 is hydrogen or R23;
or a pharmaceutically acceptable salt thereof.
Suitable heteroaryl moieties for R1 and R2 are 4-pyridyl, 4-pyrimidinyl, 4-quinazolinyl, 4-quinolyl, or 6-isoquinolinyl, 1-irnidazolyl, 1-benzimidazolyl and thiophene. Preferably the heteroaryl ring is a 4-pyridyl, 4-pyrimidinyl, 4-quinazolinyl, 4-quinolyl, or 6-isoquinolinyl ring. More preferably the heteroaryl group is a 4-pyridyl, or 4-pyrimidinyl ring. Preferably, the 4-pyridyl group is substituted in the 2-position and the 4-pyrimidinyl group is substituted at the 2- or 4-position.
Each of these heteroaryl rings may be optionally substituted with one or two substituents, each of which is independently selected from Y, NHRa, optionally substituted C1-4alkyl, halogen, hydroxyl, optionally substituted C1-4 alkoxy, optionally substituted C1-4 alkylthio, C1-4 alkylsulfmyl, CH2OR12, amino, mono and di-C1-6 alkyl substituted amino, or N(R10)C(O)Rb.
Y is suitably Y is X1xe2x80x94Ra; and X1 is oxygen or sulfur, preferably oxgyen. Ra is suitably a C1-6 alkyl, aryl, arylC1-6alkyl, heterocyclic, heterocyclylC1-6 alkyl, heteroaryl, heteroarylC1-6alkyl group, wherein each of these moieties may be optionally substituted.
Rb is suitably hydrogen, C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alyl, heteroaryl, heteroarylC1-4 alkyl, heterocyclyl, or heterocyclylC1-4 alky, wherein each of these moieties may be optionally substituted as defined herein.
When the R1 substituent is Y, and Ra is aryl, it is preferably phenyl or naphthyl. When Ra is aryl alkyl, it is preferably benzyl or napthylmethyl. When Ra is heterocyclic or heterocyclic alkyl moiety, the heterocyclic portion is preferably pyrrolindinyl, piperidine, morpholino, tetrahydropyran, tetrahydrothiopyranyl, tetrahydrothipyran-sulfinyl, tetrahydrothio-pyransulfonyl, pyrrolindinyl, indole, or piperonyl. It is noted that the heterocyclic rings herein may contain unsaturation, such as in a tryptamine ring.
The Ra aryl, heterocyclic and heteroaryl rings may be optionally substituted one or more times independently with halogen; C1-4 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted alkyl, such as CF3; hydroxy; hydroxy substituted C1-4 alkyl; C1-4 alkoxy, such as methoxy or ethoxy: S(O)malkyl and S(O)maryl (wherein m is 0, 1, or 2); C(O)OR11, such as C(O)C1-4 alkyl or C(O)OH moieties; C(O)R11; xe2x80x94OC(O)Rc; Oxe2x80x94(CH2)s-Oxe2x80x94, such as in a ketal or dioxyalkylene bridge; amino; mono- and di-C1-6 alkylsubstituted amino; xe2x80x94N(R10)C(O)Rb; xe2x80x94C(O)NR10R20; cyano, nitro, or an N-heterocyclyl ring which ring has from 5 to 7 mnembers and optionally contains an additional heteroatomn selected from oxygen, sulfur or NR15; aryl, such as phenyl; an optionally substituted arylalkyl, such as benzyl or phenethyl; aryloxy, such as phenoxy; or arylalkyloxy such as benzyloxy. Wherein Rc is optionally substituted C1-6 aklyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4allcyl, heterocyclyl, or heterocyclylC1-4 alkyl moieties.
Preferably, the Ra groups include benzyl, halosubstituted benzyl, napthylmethyl, phenyl, halosubstituted phenyl, aminocarbonylphenyl, alkylphenyl, cyanophenyl, alkylthiophenyl, hydroxyphenyl, alkoxyphenyl, morpholinopropyl, piperonyl, piperidin-4-yl, alkyl substituted piperidine, such as 1-methyl piperidine, or 2,2,6,6-tetramethylpiperidin-4-yl.
Preferably, when the substituent is NHRa then Ra is aryl, such as phenyl or napthyl; arylalkyl such as benzyl or naphtylmethyl; halosubstituted arylalkyl, halosubstituted aryl; heterocyclic alkyl, such as morpholinopropyl; hydroxy alkyl; alkyl-1-piperidinearboxylate: heterocyclic, such as piperonyl, or piperidinyl; alkyl substituted heterocyclic, such as alkyl substituted piperidine; halosubstituted heterocyclic; or aryl substituted heterocyclic.
Preferably, when the R1 substituent is an optionally substituted C1-4 alkoxy or C1-4 alkylthio, the alkyl chain may be substituted by halogen, such as fluorine, chlorine, bromine or iodine; hydroxy, such as hydroxyethoxy; C1-10 alkoxy, such as a methoxymethoxy, S(O)m alkyl, wherein m is 0, 1 or 2: amino, mono and di-substituted amino, such as in the NR7R17 group, i.e. tert-butylaminoethoxy; or where the R7R17 may together with the nitrogen to which they are attached cyclize to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from O/N/S, C1-10 alkyl, cycloalkyl, or cycloalkyl alkyl group, such as methyl, ethyl, propyl, isopropyl, t-butyl, etc. or cyclopropyl methyl; or halosubstituted C1-10 alkyl, such as CF3.
Preferred substituents for the heteroaryl ring R1 is C1-4 alkyl, NH2 or monosubstituted C1-4alkyl amino, i.e. wherein both R10 and R20 are preferably hydrogen or one of R10 and R20 is hydrogen and the other is a C1-4 alkyl. Preferably, when the substituent is a C1-4 alkyl group it is methyl, and when the substitutent is the mono-substiuted amino, it is preferably xe2x80x94NH(CH3).
For the purposes herein when the RI is a 4-pyriinidinyl moiety the xe2x80x9ccorexe2x80x9d pyrimidinyl is referred to as having the formula: 
When the R1 (or R2) 4-pyrimidinyl moiety is substituted it is preferably substituted in at least one of the following position by the moiety Y3 and Y4 which are referred to herein in greater detail as optional substituents on the heteroaryl rings R1 and R2. 
As the nomenclature will change when either Y3 or Y4 is substituted, for the purposes herein when Y4 but not Y3 is the substituted position it is referred to as the 2- position. When Y3 but not Y4 is the substituted position it is referred to as the 4-position and the point of attachment of the pyrimidinyl ring is not the 6-position.
Suitable aryl groups for R2 include optionally substituted phenyl, naphth-1-yl or naphth-2-yl. Preferably R2 is an optionally substituted phenyl. These aryl rings may be optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, -naphth-1-yl or 5-naphth-2-yl substituent, is halo, cyano, xe2x80x94C(Z)NR13R14, xe2x80x94C(Z)OR23, xe2x80x94(CR1OR2O)n COR36, xe2x80x94SR15, xe2x80x94SOR15, xe2x80x94OR36, halo-substituted-C1-4 alkyl, C1-4 alkyl, xe2x80x94ZC(Z)R36, xe2x80x94NR10C(Z)R23, or xe2x80x94(CR10R20)n NR10R20 and which, for other positions of substitution, is halo, cyano, xe2x80x94C(Z)NR16R26, xe2x80x94C(Z)OR8, xe2x80x94(CR10R20)n COR8, xe2x80x94S(O)mR8, xe2x80x94OR8, halo-substituted-C1-4 alkyl, xe2x80x94C1-4 alkyl, xe2x80x94(CR10R20)nNR10C(Z)R8, xe2x80x94NHS(O)mR7, xe2x80x94NHS(O)mNR13R14, xe2x80x94NR7S(O)mR7, xe2x80x94NR7S(O)mxe2x80x2NR13R14 wherein mxe2x80x2 is 1 or 2, xe2x80x94ZC(Z)R8 or xe2x80x94(CR10R2O)nNR16R26.
Preferred substitutions for R2 when it is a 4-phenyl, 4naphth-1-yl or 5-naphth-2-yl moiety are one or two substituents each independently selected from halogen, xe2x80x94SR15, xe2x80x94SOR15, xe2x80x94OR36, or xe2x80x94(CR10R20)nNR10R20, and for other positions of substitution on these rings preferred substitution is halogen, xe2x80x94S(O)mR8, xe2x80x94OR8, (CR1OR20)nNR16R26, xe2x80x94(CR10R20)nNR10C(Z)R8 and xe2x80x94NR7S(O)mR7. More preferred substituents for the 4-position in phenyl and naphth-1-yl and on the 5-position in naphth-2-yl include halogen, especially fluoro and chloro, and xe2x80x94SR15 and S(O)R15 wherein R15 is preferably a C1-4 alkyl, more preferably methyl; of which fluoro is especially preferred. Preferred substituents for the 3-position in phenyl and naphth-1-yl include: halogen, especially chloro; xe2x80x94OR8, especially C1-4 alkoxy; amino; xe2x80x94NR10C(Z)R8, especially xe2x80x94NHCO(C1-10alkyl); and xe2x80x94NR10S(O)mR11, especially NHSO2(C1-10 alkyl). Preferably, the aryl group is an unsubstituted or substituted phenyl moiety. More preferably, it is phenyl or phenyl substituted at the 4-position with fluoro and/or substituted at the 3-position with fluoro, chloro, C1-4 alkoxy, methanesulfonamido or acetamido.
Suitably, R3 is -hydrogen, NR5R6, NHS(O)2R7, NR10C(Z)R8, NR10C(Z)NR5R6, NR10C(xe2x95x90NR11)NR5R6, or NR10C(Z)OR10; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl moieties of R5, R6, R7, R8, R10, and R11 may be optionally substituted as herein defined.
In a preferred subgenus of compounds of formula (I), R1 is 4-pyidyl, 2-alkyl-4-pyridyl, 2-NR10R20opyridyl, 4pyrirridinyl, 2-alkylfpyrimidinyl, 2xe2x80x94NR10R20-4pyrimidinyl, or 4quinolyl; R2 is an optionally substituted phenyl group. More preferably R2 is phenyl or phenyl substituted by fluoro, chloro, C1-4 alkoxy, S(O)mC1-4 alkyl, methanesulfonamido or acetamido.
Another aspect of the present invention are the novel compounds of Formula (II): 
wherein:
R1 is 4-pyridyl, 4-pyrimidinyl, 4-quinazolinyl, 4-quinolyl, or 6-isoquinolinyl, which rings are optionally substituted with one or two substituents, each of which is independently selected from Y, NHRa, optionally substituted C1-4 alkyl, halogen, hydroxyl, optionally substituted C1-4 alkoxy, optionally substituted C1-4 alkylthio, C1-4 alkylsulfinyl, CH2OR12, amino, mono and di-C1-6 alkyl substituted amino, or N(R10)C(O)Rb;
Y is X1xe2x80x94Ra;
X1 is oxygen or sulfur; p1 Ra is C1-6alkyl, aryl, arylC1-6alkyl, heterocyclic, heterocyclylC1-6 alkyl, heteroaryl, heteroarylC1-6alkyl, wherein each of these moieties may be optionally substituted;
Rb is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclyl, or heterocyclylC1-4alkyl, wherein each of these moieties may be optionally substituted;
R2 is an optionally substituted aryl or optionally substituted heteroaryl group, provided that both R1 and R2 are not the same heteroaryl group; wherein when one R2 is an optionally substituted aryl ring, the ring is substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl or 5-naphth-2-yl substituent, is halo, cyano, xe2x80x94C(Z)NR13R14, xe2x80x94C(Z)OR23, CR10R20)n COR36, xe2x80x94SR15, xe2x80x94S(O)R15, xe2x80x94OR36, halo-substituted-C1-4 alkyl, C1-4 alkyl, xe2x80x94ZC(Z)R36, xe2x80x94NR10C(Z)R23, or xe2x80x94(CR10R20)n NR10R20 and which, for other positions of substitution, is halo, cyano, xe2x80x94C(Z)NR16R26, xe2x80x94C(Z)OR8, xe2x80x94(CR10R20)n COR8, xe2x80x94S(O)mR8, xe2x80x94OR8, halo-substituted-C1-4 alkyl, xe2x80x94C1-4 alkyl, xe2x80x94(CR10R20)nNR10C(Z)R8, xe2x80x94NHS(O)mR7, xe2x80x94NHS(O)mNR13R14, xe2x80x94NR7S(O)mR7, xe2x80x94NR7S(O)mxe2x80x2NR13R14 wherein mxe2x80x2 is 1 or 2, xe2x80x94ZC(Z)R8 or xe2x80x94(CR10R20)n NR16R26; and when R2 is an optionally substituted heteroaryl group, the substituent groups include one or two substituents each of which is independently selected from C1-4allyl, halo, C1-4 alkoxy, C1-4 alkylthio, NR10R20, or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR12;
m is 0 or an integer of 1 or 2;
n is 0 or an integer of 1 or 2;
R3 and R4 are independently NR5R6, NHS(O)2R7, NR10C(Z)R8, NR10C(Z)NR5R6, NR10C(xe2x95x90NR11)NR5R6, or NR10C(Z)OR10;
R5 and R6 are each independently selected from hydrogen or optionally substituted C1-4alkyl, optionally substituted aryl or optionally substituted aryl-C1-4alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9;
Z is oxygen or sulfur;
R7 is C1-10 alkyl, C3-7 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C1-10alkyl, heteroaryl or heteroarylalkyl; wherein all of these moieties may be optionally substitued;
R8 is hydrogen, C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl C1-10alkyl, aryl, arylC1-10 alkyl, heteroaryl or heteroarylC1-10 alkyl; wherein all of these moieties may be optionally substitued;
R9 is hydrogen, xe2x80x94C(Z)R8 or optionally substituted C1-10 alkyl, S(O )2R7, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl;
R10 and R20 is each independently selected from hydrogen or C1-4 alkyl;
R11 is hydrogen, cyano, C1-4 alkyl, C3-7 cycloalkyl or aryl;
R12 is R10 or C(Z)xe2x80x94C1-4 alkyl;
R13 and R14 is each independently selected from hydrogen or C1-4 alkyl or R13 and R14 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR17;
R15 is hydrogen, C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl or NR13R14, provided that the moiety xe2x80x94SR15 is not xe2x80x94SNR13R14 and the moiety xe2x80x94S(O)R15 is not xe2x80x94SOH;
R16 and R26 is each independently selected from hydrogen or optionally substituted C1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9;
R17 is hydrogen of C(Z)xe2x80x94C1-4 alkyl;
R23 is C1-4 alkyl, halo-substituted-C1-4 alkyl, or C3-5 cycloalkyl;
R36 is hydrogen or R23;
or a pharmaceutically acceptable salt thereof.
Suitable heteroaryl moieties for R1 and R2 in Formula (II) are those as defined above for Formula (I), as are the remaining substituent groups, but for the R3 and R4 variables defined below.
Suitably, R3 and R4 are NR5R6, NHS(O)2R7, NR10C(Z)R8, NR10C(Z)NR5R6, NR10C(xe2x95x90NR11)NR5R6, or NR10C(Z)OR10; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl moieties of R7, R8, R10, R11 may be optionally substituted as defined herein. More preferably, R3 and R4 are NR5R6 and R5 and R6 are independently hydrogen or C1-4 alkyl.
In a preferred subgenus of compounds of formula (II), R1 is 4-pyridyl, 2-alkyl4-pyridyl, 2-NR10R20-4-pyridyl, 4-pyrimidinyl, 2-alkyl-4-pyrimidinyl, 2-NR10R20-4-pyrimidinyl, or 4-quinolyl; R2 is an optionally substituted phenyl group. More preferably R2 is phenyl or phenyl substituted by fluoro, chloro, C1-4 alkoxy, S(O)mC1-4 alkyl, methanesulfonamido or acetamido.
In yet another embodiment of the present invention are the novel compounds of Formula (III): 
wherein:
R1 is 4-pyridyl, 4-pyrimidinyl, 4-quinazolinyl, 4-quinolyl, or 6-isoquinolinyl, which rings are optionally substituted with one or two substituents, each of which is independently selected from Y, NHRa, optionally substituted C1-4 alkyl, halogen, hydroxyl, optionally substituted C1-4 alkoxy, optionally substituted C1-4 alkylthio, C1-4 alkylsulfinyl, CH2OR12, amino, mono and di-C1-6 alkyl substituted amino, or N(R10)C(O)Rb;
Y is X1xe2x80x94Ra;
X1 is oxygen or sulfur;
Ra is C1-6aryl, aryl, arylC1-6alkyl, heterocyclic, heterocyclylC1-6 alkyl, heteroaryl, heteroarylC1-6alkyl, wherein each of these moieties may be optionally substituted;
Rb is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclyl, or heterocyclylC1-4 akyl, wherein each of these moieties may be optionally substituted;
R2 is an optionally substituted aryl or optionally substituted heteroaryl group, provided that both R1 and R2 are not the same heteroaryl group; wherein when one R2 is an optionally substituted aryl ring, the ring is substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl or 5-naphth-2-yl substituent, is halo, cyano, xe2x80x94C(Z)NR13R14, xe2x80x94C(Z)OR23, xe2x80x94(CR11OR20)n COR36, xe2x80x94SR15, xe2x80x94S(O)R15, xe2x80x94OR36, halo-substituted-C1-4 alkyl, C1-4 alkyl, xe2x80x94ZC(Z)R36, xe2x80x94NR10C(Z)R23, or xe2x80x94(CR10R20)n NR10R20 and which, for other positions of substitution, is halo, cyano, xe2x80x94C(Z)NR16R26, xe2x80x94C(Z)OR8, xe2x80x94(CR10R20)n COR8, xe2x80x94S(O)mR8, xe2x80x94OR8, halo-substituted-C1-4 alkyl, xe2x80x94C1-4 alkyl, xe2x80x94(CR10R20)nNR10C(Z)R8, xe2x80x94NHS(O)mR7, xe2x80x94NHS(O)mNR13R14, xe2x80x94NR7S(O)mR7, xe2x80x94NR7S(O)mxe2x80x2NR13R14, xe2x80x94ZC(Z)R8 or xe2x80x94(CR10R20)n NR16R26; and when R2 is an optionally substituted heteroaryl group, the substituent groups include one or two substituents each of which is independently selected from C1-4 alkyl, halo, C1-4 alkoxy, C1-4 alkylthio, NR10R20, or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatorn selected from oxygen, sulfur or NR12;
m is 0 or an integer of 1 or 2;
mxe2x80x2 is an integer of 1 or 2;
mxe2x80x3 is an integer having a value of 1 to 10;
n is 0 or an integer of 1 or 2;
nxe2x80x2 is 0 or an integer having a value of 1 to 10;
nxe2x80x3 is an integer having a value of 1 to 10
R3 is hydrogen, C1-10 alkyl, halosubstituted C1-10 alkyl, xe2x80x94(CR10R20)nxe2x80x2Q-(Y1)t, xe2x80x94(CR10R20)nxe2x80x2 (Y2)p, xe2x80x94(CR10R20)nxe2x80x3(Y3)p, or xe2x80x94(CR10R20)mxe2x80x3 (Y4)p;
p is 0 or an integer of 1 or 2
t is an integer of 1, 2, or 3;
Q is an aryl or heteroaryl group;
Y1 is independendy selected from hydrogen, halogen, C1-5 alkyl, halo-substituted C1-5 alkyl, xe2x80x94(CR10R20)nxe2x80x2 (Y2)p, xe2x80x94(CR10R20)nxe2x80x3 (Y3)p, or xe2x80x94(CR10R20)mxe2x80x3 (Y4)p;
Y2 is halogen, xe2x80x94OR8, xe2x80x94S(O)mxe2x80x2 R18, xe2x80x94SR8, xe2x80x94S(O)mxe2x80x2OR8, xe2x80x94S(O)mNR8R9, or xe2x80x94O(CR10R20)nNR8R9, xe2x80x94ZC(O)R8, or xe2x80x94OC(Z)NR8R9;
Y3 is xe2x80x94NR8R9, xe2x80x94NR10C(Z)R8, xe2x80x94NR10C(Z)NR8R9, xe2x80x94NR10S(O)mR18, xe2x80x94N(OR21)C(Z)NR8R9, xe2x80x94N(OR21)C(Z)R8, xe2x80x94NR10C(xe2x95x90NR11)SR18, xe2x80x94NR10C(xe2x95x90NR11)NR8R9, xe2x80x94NR10C(xe2x95x90CR14R24)SR18, xe2x80x94NR10C(xe2x95x90C(R24)2)NR8R9, xe2x80x94NR10C(O)C(O)NR8R9, xe2x80x94NR10C(O)C(O)OR10, xe2x80x94NR10S(O)mCF3, or xe2x80x94NR10C(Z)OR10;
Y4 is xe2x80x94C(O)R8, xe2x80x94CO2R8, xe2x80x94CO2(CR10R20)mxe2x80x3 CONR8R9, xe2x80x94CN, xe2x80x94C(Z)NR8R9, xe2x80x94C(Z)NR8OR9, xe2x80x94C(xe2x95x90NOR21)R8, xe2x80x94C(xe2x95x90NR19)NR8R9, xe2x80x94C(xe2x95x90NOR19)NR8R9, xe2x80x94C(xe2x95x90NR19)ZR18, xe2x80x94NR10S(O)mCF3, or xe2x80x94NR10C(Z)OR10O;
R4 is hydrogen, NR5R6, NHS(O)2R7, NR10C(Z)R8, NR10C(Z)NR5R6, NR10C(xe2x95x90NR11)NR5R6, or NR10C(Z)OR10; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl moieties of R7, and R8 may be optionally substituted;
R5 and R6 are each independently selected from hydrogen or optionally substituted C1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR17;
Z is oxygen or sulfur;
R7 is C1-10 alkyl, C3-7 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C1-10 alkyl, heteroaryl or heteroarylalkyl;
R8 is hydrogen, C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl C1-10alkyl, aryl, arylC1-10 alkyl, heteroaryl or heteroarylC1-10 alkyl;
R9 is hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl or R8 and R9 may together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR17;
R10 and R20 is each independently selected from hydrogen or C1-4 alkyl; R1-11 is hydrogen, cyano, C1-4 alkyl, C3-7 cycloalkyl or aryl; R12 is R10 or C(Z)xe2x80x94C1-4 alkyl;
R13 and R14is each independently selected from hydrogen or C1-4 alkyl or R13 and R14 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR22;
R15 is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR13R14, provided that the moiety xe2x80x94SR15 is not xe2x80x94SNR13R14 and the moiety xe2x80x94S(O)R15 is not xe2x80x94SOH;
R16 and R26 is each independently selected from hydrogen or optionally substituted C1-4alkyl, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR17;
R17 is hydrogen, xe2x80x94C(Z)R8 or optionally substituted C1-10 alkyl, S(O)2R7, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl;
R18 is C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R19 is hydrogen, C1-10 alkyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
R21 is hydrogen, a pharmaceutically acceptable cation, C1-10 alkyl, C3-7 cycloalkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, or C1-10 alkanoyl;
R22 is R10 or C(Z)xe2x80x94C1-4 alkyl;
R23 is C1-4 alkyl, halo-substituted-C1-4 alkyl, or C3-5 cycloalkyl;
R24 is independently selected from hydrogen, alkyl, nitro or cyano;
R36 is hydrogen or R23;
or a pharmaceutically acceptable salt thereof.
Suitable heteroaryl moieties for R1 and R2 in Formula (III) are the same as defined above for Formula (1), as are the remaining substituent groups, but for R3 and R4 variables defined below.
Suitably, R4 is NR5R6, NHS(O)2R7, NR10C(Z)R8, NR10C(Z)NR5R6, NR10C(xe2x95x90NR11)NR5R6, or NR10C(Z)OR10; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl moieties of R5, R6, R7, R8, R10, and R11 may be optionally substituted as herein defined. More preferably R4 is NR5R6 and R5 and R6 arehydrogen or C1-4 alkyl.
Suitably, R3 is hydrogen, C1-10 alkyl, halosubstituted C1-10 alkyl, xe2x80x94(CR10R20)nxe2x80x2 Q-(Y1)t, xe2x80x94(CR10R20)nxe2x80x2 (Y2)p, xe2x80x94(CR10R20)nxe2x80x3(Y3)p, or xe2x80x94(CR10R20)mxe2x80x3(Y4)p. Preferably when R3 is xe2x80x94(CR10R20)nxe2x80x2Q-(Y1)t then Q is aryl, and t is 1. Suitably R3 is xe2x80x94(CR10R20)nxe2x80x3(Y3)p.
Y2 is suitably halogen, xe2x80x94OR8, xe2x80x94S(O)mxe2x80x2R18, xe2x80x94SR8, xe2x80x94S(O)mxe2x80x2OR8, xe2x80x94S(O)mNR8R9, or xe2x80x94O(CR10R20)nNR8R9, xe2x80x94ZC(O)R8, or xe2x80x94OC(Z)NR8R9.
Y3 is suitably xe2x80x94NR8R9, xe2x80x94NR10C(Z)R8, xe2x80x94NR10C(Z)NR8R9, xe2x80x94NR10S(O)mR18, xe2x80x94N(OR21)C(Z)NR8R9, xe2x80x94N(OR21)C(Z)R8, xe2x80x94NR10C(xe2x95x90NR11)SR18, xe2x80x94NR10C(xe2x95x90NR11)NR8R9, xe2x80x94NR10C(xe2x95x90CR14R24)SR18, xe2x80x94NR10C(xe2x95x90C(R24)2)NR8R9, xe2x80x94NR10C(O)C(O)NR8R9, xe2x80x94NR10C(O)C(O)OR10, xe2x80x94NR10S(O)mCF3, or xe2x80x94NR10C(Z)OR10.
Y4 is suitably xe2x80x94C(O)R8, xe2x80x94CO2R8, xe2x80x94CO2(CR10R20)mxe2x80x3 CONR8R9, xe2x80x94CN, xe2x80x94C(Z)NR8R9, xe2x80x94C(Z)NR8OR9, xe2x80x94C(xe2x95x90NOR21)R8, xe2x80x94C(xe2x95x90NR19)NR8R9, xe2x80x94C(xe2x95x90NOR19)NR8R9, xe2x80x94C(xe2x95x90NR19)ZR18, xe2x80x94NR10S(O)mCF3, or xe2x80x94NR10C(Z)OR10.
In all instances herein where there is an alkenyl or alkynyl moiety as a substituent group, the unsaturated linkage, i.e., the vinylene or acetylene linkage is preferably not directly attached to the nitrogen, oxygen or sulfur moieties, for instance in C(Z)NR8OR9, NR10C(Z)NR8R9, or OR8.
As used herein, for all formulas, xe2x80x9coptionally substitutedxe2x80x9d unless specified, refers to such groups as halogen, halo C1-6 alkyl, C1-6 alkyl, hydroxyl, hydroxyl substituted C1-6 alkyl, C1-6 alkoxy, S(O)mC1-6 alkyl, amino, a mono and di C1-6alkyl substituted amino, C3-7 cycloalkyl, aryl or arylalkyl wherein the cycloalkyl and aryl moieties may be optionally substituted by halogen, hydroxyl, alkoxy, S(O)mC1-6 alkyl, amino, a mono and di-C1-6alkyl substituted amino, C1-6 alkyl, or halo C1-6 akyl.
Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromc acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent Y1 in R3 comprises a carboxy group. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
The following terms, as used herein, refer to:
xe2x80x9chaloxe2x80x9dxe2x80x94all halogens, that is chloro, fluoro, bromo and iodo;
xe2x80x9cC1-10 alkylxe2x80x9d or xe2x80x9cakylxe2x80x9dxe2x80x94both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like;
The term xe2x80x9ccycloalkylxe2x80x9d is used herein to mean cyclic radicals, preferably of 3 to 7 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
The term xe2x80x9calkenylxe2x80x9d is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
xe2x80x9carylxe2x80x9dxe2x80x94phenyl and naphthyl;
xe2x80x9cheteroarylxe2x80x9d (on its own or in any combination, such as xe2x80x9cheteroaryloxyxe2x80x9d)xe2x80x94a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, thiophene, quinoline, isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimnidazole;
xe2x80x9cheterocyclicxe2x80x9d (on its own or in any combination, such as xe2x80x9cheterocyclylalkylxe2x80x9d)xe2x80x94a saturated or wholly or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, imidazolidine or pyrazolidine;
The term xe2x80x9caralkylxe2x80x9d or xe2x80x9cheteroylalkylxe2x80x9d or xe2x80x9cheterocyclicalkylxe2x80x9d is used herein to mean C1-4 alkyl as defined above unless otherwise indicated
xe2x80x9csulfinylxe2x80x9dxe2x80x94the oxide S(O) of the corresponding sulfide while the term xe2x80x9cthioxe2x80x9d refers to the sulfide.
The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racenic and optically active forms. All of these compounds are included within the scope of the present invention.
Compounds of Formula (I) may be readily prepared using procedures well known to those of skill in the art and may be prepared by analogous methods to those indicated herein below. 
While the illustration in Schemes I and II are for the preparation of a particular compound of Formula (I) (i.e., Scheme I, R1=-pyridyl, R2=4-fluorophenyl and R3=acetamide), generalization of the synthesis to groups claimed as R1 and R2 and R3 herein can be achieved by starting with the appropriate acetophenones, preparation of which are disclosed in PCT/US93/00674, now U.S. Pat. No. 5,686,455, notably Scheme I, whose disclosure is herein incorporated by reference. Conversion of the appropriate acetophenone to the corresponding enamine 2 is outlined in EP 0 531 901 A2 whose disclosure is incorporated by reference herein. Treatment of 2 with a guanidine, or a mono- or di alkyl guanidine, affords pynmidine 3 where R3 is equal to a primary, secondary or tertiary amino group, respectively. The desired guanidines are either commercially available or can be prepared by the procedure outlined in Oxley, P. et al., J. Chem. Soc., (1951), 1252 whose disclosure is incorporated by reference herein. Pyriridine 3 can be converted to additional compounds of Formula (I) wherein R3 is the corresponding sulphonamide, amide, urea, guanidine or urethane by using techniques well known to those of skill in the art of the appropriate acylating agents, such as sulfonyl chlorides, acid chlorides, isocyanates, dicyanamides and chloroformates, respectively. 
The appropriately substituted acetephone, 3-Scheme-II, is prepared by adding the anion of 4-methyl-quinoline (step b), which is prepared by treatment thereof with an alyl lithium derivative, such as n-butyl lithium, to an N-alkyl-O-alkoxybenzamide. Suitably, the other R1 moieties may be prepared in an analogous manner. Alternatively, the anion may be condensed with a benzaldehyde, to give an alcohol which is then oxidized to the ketone 3.
Compounds of Formula (II) are also pyrimidine derivatives which may be readily prepared using procedures well known to those of skill in the art and may be prepared by analogous methods to those indicated herein below. 
While the illustration in Schemes III and IV are for the preparation of a particular compound of Formula (II) (i.e., Scheme IV, R1=-pyridyl, R2=4-fluorophenyl, R4=amino and R3=hydrogen), generalization of the synthesis to groups claimed as R1 and R2 and R3 herein can be achieved by starting with the appropriate acetophenones, preparation of which are disclosed in PCT/US93100674, noteably Scheme IV, whose disclosure is incorporated by reference herein. Conversion to the corresponding enamine 2, isoxazole 3 and propanenitrile 4 is outlined in EP 0 531 901 A2 whose disclosure is incorporated by reference herein. Conversion of propanenitrile 4 is facilitated by formation of an enol ether derivative (e.g., a silyl enol ether). Subsequent treatment with guanidine, or a mono- or dialkyl guanidine, affords pyrimidine 5 where R3 is equal to a primary, secondary or tertiary amino group, respectively, and R4 is NH2. The desired substituted guanidines (resulting in R3) are either commercially available, or can be prepared by the procedure outlined in Oxley, P. et al., J. Chem. Soc., (1951), 1252. The R3 group of a pyrimidine 5 may if needed, be protected prior to derivatization, of the amino group (R4) such as noted below. Alternatively, the R3 moiety may also be de-protected and derivatized as well. Suitable derivitazation and protection techniques are well known by one of skill in the art. For instance, when R3 is a dialkyl amine, R4 can be converted to the corresponding sulphonamide, amide, urea, guanidine or urethane by using the appropriate acylating agents such as sulfonyt chlorides, acid chlorides, isocyanates, dicyanamides and chloroformates, respectively. When R3 is a primary amnine, R3 and R4 can be converted to the bis-sulphonamides, bisamides, bisureas, bisguanidines or bisurethanes by using the appropriate acylating agents such as those listed above, with appropriate separation techniques if need be. 
The appropriately substituted acetaphenone, 3 of scheme 4 is prepared by adding the anion of 4-methyl-quinoline (step b), which is prepared by treatment thereof with an alkyl lithium derivative, such as n-butyl lithium, to an N-alyl-O-allkoxybenzamide. Suitably, the other R1 moieties may be prepared in an analagous manner. Altematively, the anion may be condensed with a benzaldehyde, to give an alcohol which is then oxidised to the ketone 3.
Compounds of Formula (III) are pyrimidine derivatives which may be readily prepared using procedures well known to those of skill in the art and may be prepared by analogous methods to those indicated below. 
While the illustration in Schemes V and VI are for the preparation of a particular compound of Formula (III) (i.e., Scheme I, R1=-pyridyl, R2=4-fluorophenyl, R4=amino and R3=hydrogen), generalization of the synthesis to groups claimed as R1, R2 and R3 herein can be achieved by starting with the appropriate acetophenones, preparation of which are disclosed in PCT/US93/00674, noteably Scheme VI, whose disclosure is herein incorporated by reference. Conversion to the corresponding enamine 2, isoxazole 3 and propanenitrile 4 is outlined in EP 0 531 901 A2, whose disclosure is incorporated by reference herein. Subsequent treatment of 4 with the appropriately substituted amidine gives a substituted R3-4-amino pyrimidine of Formula (III). Alternatively, appropriately substituted amidines may be used in step (e) to produce directly compounds of Formula (III) which may then be used, as necessary, as intermediates to produce further compounds of Fonnula (III) through deriviatization. Appropriately substituted amidines may be made using the procedures such as those taught in Garigipati, R. S., Tet. Lett., (1990), 31 (14), 1969 whose disclosure is incorporated by reference herein. Pyrimidine 5 can be converted to to additional compounds of Formula (III) wherein R4 is the corresponding sulphonamide, amide, urea, guanidine or urethane by using the appropriate acylating agents such as sulfonyl chlorides. isocyanates, dicyanarnides and chloroformates, respectively. While it is recognized that in the Scheme I the R4 amino group is unsubstituted, (R5 and R6=hydrogen) the amino agroup may also be suitably converted to the mono- or di-alkyl derivative by one of skill in the art by appropriate and well known techniques. 
The appropriately substituted acetophone, 3-Scheme-6, is prepared by adding the anion of 4-methyl-quinoline (step b), which is prepared by treatment thereof with an alkyl lithium derivative, such as n-butyl lithium, to an N-alkyl-O-alkoxybenzamide. Suitably, the other R1 moieties may be prepared in an analagous manner. Alternatively, the anion may be condensed with a benzaldehyde. to give an alcohol which is then oxidised to the ketone 3.
Suitable protecting groups for use in the present invention, are well known in the art and described in many references, for instance, Protecting Groups in Organic Synthesis, Greene T W, Wiley-Interscience, New York, 1981.
Pharmaceutically acid addition salts of compounds of formula (I), (II) or (III) may be obtained in known manner, for example by treatment thereof with an appropriate amount of acid in the presence of a suitable solvent.